Development and Application of a Physiologically Based Pharmacokinetic Model for Ethanol in the Mouse

Abstract

The purpose of the present study was to develop a physiologically based pharmacokinetic (PBPK) model in the mouse and to utilize it to evaluate the relative contribution, if any, of gastric alcohol dehydrogenase (ADH) to the bioavailability of ethanol. The PBPK model developed in Swiss Webster male mice accurately simulated blood and brain ethanol concentrations following an intraperitoneal administration of 0.82 and 3.2 g of ethanol/kg body weight. Application of the model illustrated that inclusion of gastric ADH into the model provided a less accurate fit to the experimental data, and therefore gastric ADH did not contribute to the overall disposition of an orally administered ethanol dose of 0.75 g/kg. Furthermore, the model also indicated that changes in percentage cardiac output to the liver had a minimal effect on the blood ethanol concentration (BEC) time curve. The results illustrate the validity of the PBPK model developed for ethanol and demonstrate that in the Swiss Webster male mouse the bioavailability of ethanol is minimally affected, if at all, by metabolism by gastric ADH.

Alcohol‐induced memory impairment in trace fear conditioning: A hippocampus‐specific effect

“…However, analysis of the pharmacokinetics of i.p. alcohol in the mouse (Pastino et al, 1996) shows that BAC rapidly rises and peaks at about 5 min post-injection. From that point, it gradually decreases with a halflife of approximately 50 min.…”

Assessing the dose-dependency of allometric scaling performance using physiologically based pharmacokinetic modeling

“…A total of 12 chemicals was selected for inclusion in this analysis, including: benzene , carbon tetrachloride (Thrall et al, 2000), chloroform Reitz et al, 1990), diisopropylfluorophosphate (Gearhart et al, 1990(Gearhart et al, , 1994, ethanol (Pastino et al, 1996(Pastino et al, , 1997Pastino and Conolly, 2000), ethylene oxide (Csanady et al, 2000), methylene chloride (Andersen et al, 1987, methylmercury (Young et al, 2001;Luecke et al, 1997), styrene (Csanady et al, 1994), tetrachloroethene (Reitz et al, 1996a), trichloroethene , and vinyl chloride (Reitz et al, 1996b). All of the PBPK models are based upon the structure and coding as described by Ramsey and Andersen (1984) for styrene.…”

“…PBPK model codes for all chemicals are generally available upon (Thrall et al, 2000) 1206 1293 10 None None None In vitro b Chloroform Reitz et al, 1990) (Gearhart et al, 1990(Gearhart et al, , 1994 None None None 1 (iv) 1.1 (iv) 0.054 (im) Allometric scaling (SF ¼ 0.7) Ethanol (Pastino et al, 1996(Pastino et al, , 1997Pastino and Conolly, 2000) 600 600 8491 750 1000 None In vivo Ethylene oxide (Csanady et al, 2000) 300 1350 14 1.9 (ip) 0.900 (ip) None Allometric scaling (SF ¼ 0.67) Methylene chloride (Andersen et al, 1987 10,000 3000 986 50 (iv) 10 (iv) None In vivo…”

“…64-17-5 (Pastino et al, 1996Pastino and Conolly, 2000) The pharmacokinetics of inhaled ethanol were described by Pastino et al (1997) for rats, mice, and humans. The pharmacokinetics of ingested ethanol in mice and rats were described in Pastino et al (1996) and Pastino and Conolly (2000). published a model for human ingestion of ethanol, but this model contained a modified description of uptake from the gastrointestinal tract, compared to rat and mouse models.…”

“…Rather than use different model structures for rodents and humans, scientists at The Sapphire Group extended the rodent oral model to humans (as described below). V max for mice was determined from the best fit to blood concentrations following ip administration of ethanol and validated based on blood or brain ethanol concentrations following ip, iv, and oral administration of ethanol (Pastino et al, 1996). V max for rats was determined from the best fit to blood concentrations following iv administration of ethanol and V max for humans was obtained from the literature (Pastino et al, 1997).…”